The major objects of the proposed research are to devise new, improved, practical methods of peptide and phosphate ester bond formation and to develop new amine, hydroxyl, carboxyl, and phosphate protecting groups for use in protein and polynucleotide synthesis. Recent advances include the invention of the vinyloxycarbonyl method of amino and hydroxyl protection and the use of highly activated reagents to convert peptide acids to racemization resistant, stabilized active esters. A new method for peptide synthesis via a combination amino protecting-activating group with rearrangement is being developed. The vinyloxycarbonyl method of selective, tertiary amine dealkylation invented in these laboratories is being applied to various problems of pharmaceutical significance. Recent advances include improved syntheses of the important narcotic antagonists, naloxone and naltrexone, and related synthetic analgesics. The use of substituted vinyl chloroformates in both amine protection and amine N-dealkylation is under study. Another object is the use of new knowledge on heteroaromatic C-H acidities and the WXYZ scission hypothesis developed in this laboratory: 1) in the facile preparation of a variety of new, potentially useful heterocycles, and 2) in the determination of mechanisms of biological and pharmaceutical activity. A new selective approach to 5-unsubstituted isoxazoles using a new cyclopropanol synthesis is being developed.